ABSTRACT Multiple epidemiological and experimental studies report that acute or chronic exposure to air pollution is associated with adverse cardiovascular events including myocardial ischemia, stroke, arrhythmias, heart failure, sudden cardiac arrest and atherogenesis. These effects of air pollution are most strongly correlated with fine particulate matter (PM2.5) fraction which is generated directly from the combustion of fossil fuels and is found in automobile exhaust, wood or coal smoke and industrial emissions. However, the mechanisms by which PM2.5 induces cardiovascular injury remain unclear and the pathophysiological conditions and co-exposures that determine individual susceptibility to PM2.5 toxicity have not been identified. Our previous work has shown that in young healthy adults, exposure to PM2.5 is associated with inflammation, decreases in vascular reparative circulating angiogenic cells (CACs), and changes in cytokine/growth factor profiles consistent with an inhibition of angiogenesis. In addition, we found increased levels of circulating endothelial microparticles, evidence of subclinical vascular injury. We obtained similar results in mouse exposure studies, which show that exposure to concentrated ambient particles depletes circulating angiogenic cells, and leads to defective hematopoiesis and functional defects in bone marrow-derived cells. In pilot experiments, we have found that these PM2.5-induced defects in mice could be prevented by treatment with the endogenous nucleophile carnosine, which quenches reactive oxygen species and removes toxic products of lipid peroxidation. Furthermore, in a human cohort with mild-to-moderate CVD risk, we also found that those with high CVD risk are more susceptible to the effects of PM2.5 and that individuals with high carnosine levels are relatively impervious to the adverse cardiovascular effects of PM2.5 exposure. Thus we hypothesize that individual risk factors determine cardiovascular susceptibility to PM2.5 and that means to limit electrophiles/oxidative stress will mitigate the adverse consequences of PM2.5 exposure. These ideas will be tested in three Aims. In the first we will assess the impact of PM2.5 exposure on vascular function (arterial stiffness, flow-mediated dilation, peripheral artery tone) in a population with mild-to- moderate CVD risk and determine whether exposure exacerbates composite CVD risk and whether changes inflammation, oxidative stress, or thrombosis are associated with PM2.5-induced vascular dysfunction. In the second Aim, we will determine whether the relationship between vascular injury and dysfunction is mediated by individual-level demographic characteristics (e.g., sex, age, ethnicity), co-exposure to gaseous pollutants, or systemic levels of carnosine. In the third Aim, we will enroll a subset of individuals with inherently low carnosine levels, and determine whether daily, oral supplementation with carnosine attenuates the association between PM2.5 exposure and vascular dysfunction as well as PM2.5 -induced changes in biomarkers of cardiovascular injury and indices of cardiovascular function. The results of this project will provide better estimates of CVD burden due to PM2.5 exposure, identify specific risk factors that increase susceptibility to PM2.5-induced injury, and assess the efficacy of carnosine in attenuating PM2.5 toxicity. Findings of this project could potentially lead to the development of a novel and practical therapeutic intervention to prevent PM2.5 toxicity.